Positron emission tomography (PET) is an inherently quantitative medical imaging technique. When combined with radiopharmaceuticals that provide valuable information on the state of malignancies, PET is a potentially powerful imaging modality for assessing response to new cancer therapies in multi-center clinical trials. Manufacturers of commercial PET scanner systems, however, understandably strive to generate higher quality diagnostic (i.e. detection task optimized) images to achieve market differentiation, but not necessarily the most accurate quantitative data. Recent advances in image reconstruction algorithms enhance image quality, but have paradoxically increased quantitative differences between PET scanners. The resulting variations in quantitative accuracy confound the comparisons of data within multi-center clinical trials. National and international efforts have been initiated to standardize protocols that impact PET quantitation. However, there has been limited effort to harmonize image reconstruction methodologies and parameters to resolve the problem of the substantial variability in PET image accuracy in multi-center trials. This size- and scanner-dependent variability degrades the quality of clinical trials by requiring more patient accrual and/or leading to inconclusive results in tests of badly needed cancer therapies. The proposed project will solve this problem through a combination of rigorous NIST traceable calibration standards combined with the development of an industry-supported harmonized PET image reconstruction paradigm providing quantitatively accurate and reproducible measurements with known errors characteristics. The project is supported by all three major PET/CT scanner manufacturers, facilitated through the Society of Nuclear Medicine's Clinical Trials Network, and will be primarily performed by three leading PET/CT academic institutions with extensive experience in quantitative imaging and established track records of substantial collaboration with the three manufacturers. Data will also be collected from other PET centers as needed to provide representative data and harmonized reconstruction solutions for the full range of 17 different current vintage PET/CT scanners.